FONDAPARINUX SODIUM DR REDDYS 5MG/0.4ML SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE
Active substance(s): FONDAPARINUX SODIUM
NAME OF THE MEDICINAL PRODUCT
Fondaparinux sodium Dr. Reddy’s 5 mg/0.4 ml Solution For Injection in PreFilled Syringe
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each pre-filled syringe (0.4 ml) contains 5 mg of fondaparinux sodium.
Excipient(s) with known effect: Contains less than 1 mmol of sodium (23 mg)
per dose, and therefore is essentially sodium free.
For the full list of excipients, see section 6.1.
Solution for injection in pre-filled syringe.
The solution is a clear and colourless to slightly yellow liquid.
pH value: between 5.7 and 7.5.
Osmolality: between 255 and 315 mOsm/kg of water.
Treatment of adults with acute Deep Vein Thrombosis (DVT) and treatment of acute
Pulmonary Embolism (PE), except in haemodynamically unstable patients or patients
who require thrombolysis or pulmonary embolectomy.
Posology and method of administration
The recommended dose of fondaparinux is 7.5 mg (patients with body weight
≥ 50, ≤ 100kg) once daily administered by subcutaneous injection. For patients
with body weight < 50 kg, the recommended dose is 5 mg. For patients with
body weight > 100 kg, the recommended dose is 10 mg.
Treatment should be continued for at least 5 days and until adequate oral
anticoagulation is established (International Normalised Ratio 2 to 3).
Concomitant oral anticoagulation treatment should be initiated as soon as
possible and usually within 72 hours. The average duration of administration
in clinical trials was 7 days and the clinical experience from treatment beyond
10 days is limited.
Elderly patients - No dosing adjustment is necessary. In patients ≥75 years,
fondaparinux should be used with care, as renal function decreases with age
(see section 4.4).
Renal impairment - Fondaparinux should be used with caution in patients with
moderate renal impairment (see section 4.4).
There is no experience in the subgroup of patients with both high body weight
(>100 kg) and moderate renal impairment (creatinine clearance 30-50 ml/min).
In this subgroup, after an initial 10 mg daily dose, a reduction of the daily dose
to 7.5 mg may be considered, based on pharmacokinetic modelling (see
Fondaparinux should not be used in patients with severe renal impairment
(creatinine clearance < 30 ml/min) (see section 4.3).
Hepatic impairment - No dosing adjustment is necessary in patients with either
mild or moderate hepatic impairment. In patients with severe hepatic
impairment, fondaparinux should be used with care as this patient group has
not been studied (see sections 4.4 and 5.2).
Paediatric population - Fondaparinux is not recommended for use in children
below 17 years of age due to a lack of data on safety and efficacy (see sections
5.1 and 5.2).
Method of administration
Fondaparinux is administered by deep subcutaneous injection while the patient
is lying down. Sites of administration should alternate between the left and the
right anterolateral and left and right posterolateral abdominal wall. To avoid
the loss of medicinal product when using the pre-filled syringe do not expel
the air bubble from the syringe before the injection. The whole length of the
needle should be inserted perpendicularly into a skin fold held between the
thumb and the forefinger; the skin fold should be held throughout the
For additional instructions for use and handling and disposal see section 6.6.
- hypersensitivity to the active substance or to any of the excipients listed in
active clinically significant bleeding
acute bacterial endocarditis
severe renal impairment defined by creatinine clearance < 30 ml/min.
Special warnings and precautions for use
Fondaparinux is intended for subcutaneous use only. Do not administer
There is limited experience from treatment with fondaparinux in
haemodynamically unstable patients and no experience in patients requiring
thrombolysis, embolectomy or insertion of a vena cava filter.
Fondaparinux should be used with caution in patients who have an increased
risk of haemorrhage, such as those with congenital or acquired bleeding
disorders (e.g. platelet count <50,000/mm3), active ulcerative gastrointestinal
disease and recent intracranial haemorrhage or shortly after brain, spinal or
ophthalmic surgery and in special patient groups as outlined below.
As for other anticoagulants, fondaparinux should be used with caution in
patients who have undergone recent surgery (<3 days) and only once surgical
haemostasis has been established.
Agents that may enhance the risk of haemorrhage should not be administered
concomitantly with fondaparinux. These agents include desirudin, fibrinolytic
agents, GP IIb/IIIa receptor antagonists, heparin, heparinoids, or Low
Molecular Weight Heparin (LMWH). During treatment of VTE, concomitant
therapy with vitamin K antagonist should be administered in accordance with
the information of Section 4.5. Other antiplatelet medicinal products
(acetylsalicylic acid, dipyridamole, sulfinpyrazone, ticlopidine or clopidogrel),
and NSAIDs should be used with caution. If co- administration is essential,
close monitoring is necessary.
Spinal / Epidural anaesthesia
In patients receiving fondaparinux for treatment of VTE rather than
prophylaxis, spinal/epidural anaesthesia in case of surgical procedures should
not be used.
The elderly population is at increased risk of bleeding. As renal function
generally decreases with age, elderly patients may show reduced elimination
and increased exposure of fondaparinux (see section 5.2). Incidences of
bleeding events in patients receiving the recommended regimen in the
treatment of DVT or PE and aged <65 years, 65-75 and >75 years were 3.0 %,
4.5 % and 6.5 %, respectively. The corresponding incidences in patients
receiving the recommended regimen of enoxaparin in the treatment of DVT
were 2.5%, 3.6% and 8.3% respectively, while the incidences in patients
receiving the recommended regimen of UFH in the treatment of PE were
5.5%, 6.6% and 7.4%, respectively. Fondaparinux should be used with caution
in elderly patients (see section 4.2).
Low body weight
Clinical experience is limited in patients with body weight <50 kg.
Fondaparinux should be used with caution at a daily dose of 5 mg in this
population (see sections 4.2 and 5.2).
The risk of bleeding increases with increasing renal impairment. Fondaparinux
is known to be excreted mainly by the kidney. Incidences of bleeding events in
patients receiving the recommended regimen in the treatment of DVT or PE
with normal renal function, mild renal impairment, moderate renal impairment
and severe renal impairment were 3.0 % (34/1,132), 4.4 % (32/733), 6.6%
(21/318), and 14.5 % (8/55) respectively. The corresponding incidences in
patients receiving the recommended regimen of enoxaparin in the treatment of
DVT were 2.3% (13/559), 4.6% (17/368), 9.7% (14/145) and 11.1% (2/18)
respectively, and in patients receiving the recommended regimen of
unfractionated heparin in the treatment of PE were 6.9% (36/523), 3.1%
(11/352), 11.1% (18/162) and 10.7% (3/28), respectively.
Fondaparinux is contra-indicated in severe renal impairment (creatinine
clearance <30 ml/min) and should be used with caution in patients with
moderate renal impairment (creatinine clearance 30-50 ml/min). The duration
of treatment should not exceed that evaluated during clinical trial (mean 7
days) (see sections 4.2, 4.3 and 5.2).
There is no experience in the subgroup of patients with both high body weight
(>100 kg) and moderate renal impairment (creatinine clearance 30-50 ml/min).
Fondaparinux should be used with care in these patients. After an initial 10 mg
daily dose, a reduction of the daily dose to 7.5 mg may be considered, based
on pharmacokinetic modelling (see section 4.2).
Severe hepatic impairment
The use of fondaparinux should be considered with caution because of an
increased risk of bleeding due to a deficiency of coagulation factors in patients
with severe hepatic impairment (see section 4.2).
Patients with Heparin Induced Thrombocytopenia
Fondaparinux should be used with caution in patients with a history of HIT.
The efficacy and safety of fondaparinux have not been formally studied in
patients with HIT type II. Fondaparinux does not bind to platelet factor 4 and
does not cross-react with sera from patients with Heparin Induced
Thrombocytopenia (HIT) type II. However, rare spontaneous reports of HIT
in patients treated with fondaparinux have been received. To date a causal
association between treatment with fondaparinux and the occurrence of HIT
has not been established.
Interaction with other medicinal products and other forms of interaction
Bleeding risk is increased with concomitant administration of fondaparinux
and agents that may enhance the risk of haemorrhage (see section 4.4).
In clinical studies performed with fondaparinux, oral anticoagulants (warfarin)
did not interact with the pharmacokinetics of fondaparinux; at the 10 mg dose
used in the interaction studies, fondaparinux did not influence the
anticoagulation monitoring (INR) activity of warfarin.
Platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam) and digoxin did
not interact with the pharmacokinetics of fondaparinux. At the 10 mg dose
used in the interaction studies, fondaparinux did not influence the bleeding
time under acetylsalicylic acid or piroxicam treatment, nor the
pharmacokinetics of digoxin at steady state.
Fertility, pregnancy and lactation
No clinical data on exposed pregnancies are available. Animal studies are
insufficient with respect to effects on pregnancy, embryo/foetal development,
parturition and postnatal development because of limited exposure.
Fondaparinux should not be prescribed to pregnant women unless clearly
Fondaparinux is excreted in rat milk but it is not known whether fondaparinux
is excreted in human milk. Breastfeeding is not recommended during
treatment with fondaparinux. Oral absorption by the child is however unlikely.
There are no data available on the effect of fondaparinux on human fertility.
Animal studies do not show any effect on fertility.
Effects on ability to drive and use machines
No studies on the effect on the ability to drive and to use machines have been
The most commonly reported serious adverse reactions reported with
fondaparinux are bleeding complications (various sites including rare cases of
intracranial/ intracerebral and retroperitoneal bleedings). Fondaparinux should
be used with caution in patients who have an increased risk of haemorrhage
(see section 4.4).
The safety of fondaparinux has been evaluated in 2,517 patients treated for
Venous Thrombo-Embolism and treated with fondaparinux for an average of 7
days. The most common adverse reactions were bleeding complications (see
The adverse reactions reported by the investigator as at least possibly related
to fondaparinux are presented within each frequency grouping (very common
≥ 1/10; common: ≥1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ≥
1/10,000 to <1/1,000; very rare <1/10,000) and system organ class by
decreasing order of seriousness.
System organ class
Adverse reactions in patients treated for VTE1
Common: bleeding (gastrointestinal, haematuria,
haematoma, epistaxis, haemoptysis, uterovaginal haemorrhage, haemarthrosis, ocular,
Uncommon: anaemia, thrombocytopaenia
Rare: other bleeding (hepatic,
Rare: allergic reaction (including very rare reports
of angioedema, anaphylactoid/anaphylactic
Rare: non-protein-nitrogen (Npn)2 increased
Uncommon: nausea, vomiting
Rare: abdominal pain
Hepatobiliary disorders Uncommon: abnormal liver function, hepatic
Rare: rash erythematous, pruritus
Uncommon: pain, oedema,
Rare: reaction at injection site
Isolated AEs have not been considered except if they were medically
Npn stands for non-protein-nitrogen such as urea, uric acid, amino
In post marketing experience, rare cases of gastritis, constipation, diarrhoea
and bilirubinaemia have been reported.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme, website:
Fondaparinux doses above the recommended regimen may lead to an
increased risk of bleeding. There is no known antidote to fondaparinux.
Overdose associated with bleeding complications should lead to treatment
discontinuation and search for the primary cause. Initiation of appropriate
therapy such as surgical haemostasis, blood replacements, fresh plasma
transfusion, plasmapheresis should be considered.
Pharmacotherapeutic group: antithrombotic agents. ATC code: B01AX05
Fondaparinux is a synthetic and selective inhibitor of activated Factor X (Xa).
The antithrombotic activity of fondaparinux is the result of antithrombin III
(antithrombin) mediated selective inhibition of Factor Xa. By binding
selectively to antithrombin, fondaparinux potentiates (about 300 times) the
innate neutralization of Factor Xa by antithrombin. Neutralisation of Factor Xa
interrupts the blood coagulation cascade and inhibits both thrombin formation
and thrombus development. Fondaparinux does not inactivate thrombin
(activated Factor II) and has no effects on platelets.
At the doses used for treatment, fondaparinux does not, to a clinically relevant
extent, affect routine coagulation tests such as activated partial thromboplastin
time (aPTT), activated clotting time (ACT) or prothrombin time
(PT)/International Normalised Ratio (INR) tests in plasma nor bleeding time
or fibrinolytic activity. However, rare spontaneous reports of aPTT
prolongation have been received. At higher doses, moderate changes in aPTT
can occur. At the 10 mg dose used in interaction studies, fondaparinux did not
significantly influence the anticoagulation activity (INR) of warfarin.
Fondaparinux does not cross-react with sera from patients with heparininduced thrombocytopaenia.
The fondaparinux clinical program in treatment of Venous Thromboembolism
was designed to demonstrate the efficacy of fondaparinux for the treatment of
deep vein thrombosis (DVT) and pulmonary embolism (PE). Over 4,874
patients were studied in controlled Phase II and III clinical studies.
Treatment of Deep Venous Thrombosis
In a randomised, double-blind, clinical trial in patients with a confirmed
diagnosis of acute symptomatic DVT, fondaparinux 5 mg (body weight < 50
kg), 7.5 mg (body weight ≥ 50 kg, ≤ 100 kg) or 10 mg (body weight >100 kg)
SC once daily was compared to enoxaparin sodium 1 mg/kg SC twice daily. A
total of 2,192 patients were treated; for both groups, patients were treated for
at least 5 days and up to 26 days (mean 7 days). Both treatment groups
received Vitamin K antagonist therapy usually initiated within 72 hours after
the first study drug administration and continued for 90 ± 7 days, with regular
dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was
the composite of confirmed symptomatic recurrent non-fatal VTE and fatal
VTE reported up to Day 97. Treatment with fondaparinux was demonstrated
to be non-inferior to enoxaparin (VTE rates 3.9% and 4.1%, respectively).
Major bleeding during the initial treatment period was observed in 1.1% of
fondaparinux patients, compared to 1.2% with enoxaparin.
Treatment of Pulmonary Embolism
A randomised, open-label, clinical trial was conducted in patients with acute
symptomatic PE. The diagnosis was confirmed by objective testing (lung scan,
pulmonary angiography or spiral CT scan).
Patients who required thrombolysis or embolectomy or vena cava filter were
excluded. Randomised patients could have been pre-treated with UFH during
the screening phase but patients treated for more than 24 hours with
therapeutic dose of anticoagulant or with uncontrolled hypertension were
excluded. Fondaparinux 5 mg (body weight < 50 kg), 7.5 mg (body weight ≥
50kg, ≤ 100 kg) or 10 mg (body weight >100 kg) SC once daily was compared
to unfractionated heparin IV bolus (5,000 IU) followed by a continuous IV
infusion adjusted to maintain 1.5–2.5 times aPTT control value. A total of
2,184 patients were treated; for both groups, patients were treated for at least 5
days and up to 22 days (mean 7 days). Both treatment groups received
Vitamin K antagonist therapy usually initiated within 72 hours after the first
study drug administration and continued for 90 ± 7 days, with regular dose
adjustments to achieve an INR of 2-3. The primary efficacy endpoint was the
composite of confirmed symptomatic recurrent non-fatal VTE and fatal VTE
reported up to Day 97. Treatment with fondaparinux was demonstrated to be
non-inferior to unfractionated heparin (VTE rates 3.8% and 5.0%,
Major bleeding during the initial treatment period was observed in 1.3% of
fondaparinux patients, compared to 1.1% with unfractionated heparin.
A pilot dose-finding and pharmacokinetic study of fondaparinux in
children with deep vein thrombosis
In an open-label study, 24 paediatric patients (n=10, age 1 to ≤ 5 years weight range
8-20 kg; n=7, age 6 to ≤ 12 years weight range 17-47 kg and n=7 age 13 to ≤ 18 years
weight range 47-130 kg) diagnosed with venous thrombosis at study entry were
administered fondaparinux. The majority of patients were Hispanic (67%) and 58%
were male. Fondaparinux was administered at an initial dose of 0.1 mg/kg
subcutaneously once daily and dosing was adjusted to achieve peak fondaparinux
sodium concentrations of 0.5 to 1 mg/L after 4 hours. The median duration of
treatment in this study was 3.5 days. The majority of patients (88%) achieved target
fondaparinux concentrations at 4 hours after the first dose of fondaparinux. Two
patients had reports of bleeding during the study. One experienced hypertensive
encephalopathy accompanied by intracranial bleeding on day 5 of therapy resulting in
fondaparinux discontinuation. Minor gastrointestinal bleeding was reported in another
patient on day 5 of therapy which resulted in temporary discontinuation of
fondaparinux. No conclusion can be drawn with regard to clinical efficacy in this
The pharmacokinetics of fondaparinux sodium are derived from fondaparinux
plasma concentrations quantified via anti factor Xa activity. Only
fondaparinux can be used to calibrate the anti-Xa assay (the international
standards of heparin or LMWH are not appropriate for this use). As a result,
the concentration of fondaparinux is expressed as milligrams (mg).
After subcutaneous dosing, fondaparinux is completely and rapidly absorbed
(absolute bioavailability 100%). Following a single subcutaneous injection of
fondaparinux 2.5 mg to young healthy subjects, peak plasma concentration
(mean Cmax = 0.34 mg/l) is obtained 2 hours post-dosing. Plasma
concentrations of half the mean Cmax values are reached 25 minutes postdosing.
In elderly healthy subjects, pharmacokinetics of fondaparinux is linear in the
range of 2 to 8 mg by subcutaneous route. Following once daily dosing, steady
state of plasma levels is obtained after 3 to 4 days with a 1.3-fold increase in
Cmax and AUC.
Mean (CV%) steady state pharmacokinetic parameters estimates of
fondaparinux in patients undergoing hip replacement surgery receiving
fondaparinux 2.5 mg once daily are: Cmax (mg/l) - 0.39 (31%), Tmax (h) - 2.8
(18%) and Cmin (mg/l) -0.14 (56%). In hip fracture patients, associated with
their increased age, fondaparinux steady state plasma concentrations are: Cmax
(mg/l) - 0.50 (32%), Cmin (mg/l) - 0.19 (58%).
In DVT and PE treatment, patients receiving fondaparinux 5 mg (body weight
<50 kg), 7.5 mg (body weight 50-100 kg inclusive) and 10 mg (body weight
>100 kg) once daily, the body weight-adjusted doses provide similar exposure
across all body weight categories. The mean (CV%) steady state
pharmacokinetic parameters estimates of fondaparinux in patients with VTE
receiving the fondaparinux proposed dose regimen once daily are: Cmax (mg/l)
- 1.41 (23 %), Tmax (h) – 2.4 (8%) and Cmin (mg/l) -0.52 (45 %). The
associated 5th and 95th percentiles are, respectively, 0.97 and 1.92 for Cmax
(mg/l), and 0.24 and 0.95 for Cmin (mg/l).
The distribution volume of fondaparinux is limited (7-11 litres). In vitro,
fondaparinux is highly and specifically bound to antithrombin protein with a
dose-dependant plasma concentration binding (98.6% to 97.0% in the
concentration range from 0.5 to 2 mg/l). Fondaparinux does not bind
significantly to other plasma proteins, including platelet factor 4 (PF4).
Since fondaparinux does not bind significantly to plasma proteins other than
antithrombin, no interaction with other medicinal products by protein binding
displacement are expected.
Although not fully evaluated, there is no evidence of fondaparinux metabolism
and in particular no evidence for the formation of active metabolites.
Fondaparinux does not inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9,
CYP2C19, CYP2D6, CYP2E1 or CYP3A4) in vitro. Thus, fondaparinux is not
expected to interact with other medicinal products in vivo by inhibition of
The elimination half-life (t½) is about 17 hours in healthy young subjects and
about 21 hours in healthy elderly subjects. Fondaparinux is excreted to 64 – 77
% by the kidney as unchanged compound.
Paediatric patients - Limited data are available in paediatric patients (see
Elderly patients - Renal function may decrease with age and thus, the
elimination capacity for fondaparinux may be reduced in elderly. In patients
>75 years undergoing orthopaedic surgery and receiving fondaparinux 2.5 mg
once daily, the estimated plasma clearance was 1.2 to 1.4 times lower than in
patients <65 years. A similar pattern is observed in DVT and PE treatment
Renal impairment - Compared with patients with normal renal function
(creatinine clearance > 80 ml/min) undergoing orthopaedic surgery and
receiving fondaparinux 2.5 mg once daily, plasma clearance is 1.2 to 1.4 times
lower in patients with mild renal impairment (creatinine clearance 50 to 80
ml/min) and on average 2 times lower in patients with moderate renal
impairment (creatinine clearance 30 to 50 ml/min). In severe renal impairment
(creatinine clearance <30 ml/min), plasma clearance is approximately 5 times
lower than in normal renal function. Associated terminal half-life values were
29 h in moderate and 72 h in patients with severe renal impairment. A similar
pattern is observed in DVT and PE treatment patients.
Body weight - Plasma clearance of fondaparinux increases with body weight
(9% increase per 10 kg).
Gender - No gender differences were observed after adjustment for body
Race - Pharmacokinetic differences due to race have not been studied
prospectively. However, studies performed in Asian (Japanese) healthy
subjects did not reveal a different pharmacokinetic profile compared to
Caucasian healthy subjects. Similarly, no plasma clearance differences were
observed between black and Caucasian patients undergoing orthopaedic
Hepatic impairment - Following a single, subcutaneous dose of fondaparinux
in subjects with moderate hepatic impairment (Child-Pugh Category B), total
(i.e., bound and unbound) Cmax and AUC were decreased by 22% and 39%,
respectively, as compared to subjects with normal liver function. The lower
plasma concentrations of fondaparinux were attributed to reduced binding to
ATIII secondary to the lower ATIII plasma concentrations in subjects with
hepatic impairment thereby resulting in increased renal clearance of
fondaparinux. Consequently, unbound concentrations of fondaparinux are
expected to be unchanged in patients with mild to moderate hepatic
impairment, and therefore, no dose adjustment is necessary based on
The pharmacokinetics of fondaparinux has not been studied in patients with
severe hepatic impairment (see sections 4.2 and 4.4).
Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional
studies of safety pharmacology and genotoxicity. The repeated dose and
reproduction toxicity studies did not reveal any special risk but did not provide
adequate documentation of safety margins due to limited exposure in the
List of excipients
Water for injections
Hydrochloric acid (for pH-adjustment)
Sodium hydroxide (for pH-adjustment)
In the absence of compatibility studies, this medicinal product must not be
mixed with other medicinal products.
Special precautions for storage
This medicinal product does not require any special storage conditions.
Nature and contents of container
Type I clear glass barrel (1 ml) affixed with a needle and stoppered with a
chlorobutyl elastomer plunger stopper, packed in tray pack in a carton.
Fondaparinux is available in pack sizes of 2, 7, 10, 20 and 30 pre-filled
Not all pack sizes may be marketed.
The different strengths of the medicinal product can be identified by a
different coloured plunger rod:
Fondaparinux sodium 5 mg/0.4 ml: syringe with an orange plunger rod and an
automatic safety system
Special precautions for disposal
The subcutaneous injection is administered in the same way as with a classical
Parenteral solutions should be inspected visually for particulate matter and
discoloration prior to administration.
Instruction on self-administration is included in the Package Leaflet.
The rigid needle shield of the Fondaparinux sodium 5 mg/0.4 ml solution for
injection, pre-filled syringe is used to protect from needle stick injuries
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.
This medicinal product is for single use only.
MARKETING AUTHORISATION HOLDER
Dr. Reddy’s Laboratories (UK) Ltd.
6 Riverview Road
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT
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